Process for preparing oxycodone having reduced levels of 14-hydroxycodeinone

ABSTRACT

The present invention is directed to processes for preparing oxycodone base and oxycodone hydrochloride compositions having less than 10 ppm of 14-hydroxycodeinone.

CROSS REFERENCE TO RELATED APPLICATION

This application is a continuation of U.S. application Ser. No.11/949,829, filed Dec. 4, 2007, now U.S. Pat. No. 7,906,647, whichclaims priority from U.S. Provisional Application Ser. No. 60/872,654,filed on Dec. 4, 2006, the contents of which are hereby incorporated byreference in their entirety.

FIELD OF THE INVENTION

The present invention relates to processes for reducing the amount of14-hydroxycodeinone in an oxycodone preparation.

BACKGROUND OF THE INVENTION

Oxycodone is a semi-synthetic, μ-opioid receptor specific ligand withclear agonist properties.¹ In man, oxycodone may produce any of avariety of effects including analgesia. Parenteral oxycodone was usedmainly for the treatment of acute postoperative pain whereascombinations, for example oxycodone and acetaminophen, were used formoderate pain. ¹ E. Kalso, Journal of Pain and Symptom Management,Volume 29, Issue, Supplement 1, May 2005, 47-56

Examples of immediate release (IR) products containing oxycodone includePercocet®, Percodan®, Roxocet®, and generic equivalents thereof.Examples of sustained-release (SR) dosage forms include Oxycontin® andgeneric equivalents thereof.

Oxycodone is most commonly derived from thebaine, a minor alkaloid inthe papaver somniferum poppy, and from thebaine analogues prepared fromcodeinone 14-Hydroxycodeinone is the immediate precursor to oxycodone inthese syntheses.

Thebaine can be obtained from extraction from the poppy plant papaversomniferum. However, since morphine is the major alkaloid, whichaccumulates in the capsules of the papaver somniferum plant, the supplyof thebaine from this source is limited to some fraction of the demandfor morphine. The major source of natural thebaine currently is theconcentrated poppy straw (CPS) from a stably reproducing papaversomniferum plant which has been exposed to a mutagenizing agent suchthat the straw contains thebaine and oripavine constituting about 50% byweight or greater of the alkaloid combination consisting of morphine,codeine, thebaine and oripavine². ² A. J Fist, C. J. Byrne and W. L.Gerlach, US 2004/0197428 and U.S. Pat. Nos. 6,723,894, 6,376,221, and6,067,749

Thebaine has also been prepared by total synthesis routes, which aredifficult and expensive³. Thebaine has also been prepared by themethylation of codeinone in the presence of strong base^(4,5) andoxidation of codeine methylether⁶. ³ U.S. Pat. No. 4,613,668 and U.S.Pat. No. 4,795,813⁴ A. Coop and K. Rice, Heterocycles, 49, 1998, 43-47.⁵B. Mudryk, C. Sapino, A. Sebastian, EP 0889045 A1, U.S. Pat. No.6,365,742 B1⁶ R. Barber and H. Rapaport, U.S. Pat. No. 4,045,440

Purified thebaine is normally used for conversion to oxycodone but theuse of thebaine CPS directly for the manufacture of oxycodone has alsobeen disclosed^(7,8). ⁷ See claims 9 and 10 of A. J. Fist, C. J. Byrne &W. L. Gerlach, U.S. Pat. No. 6,376,221 B1⁸ C. A. Francis, Z. Lin, C. A.Kaldahl, K. G. Antczak, V. Kumar, U.S. Pat. No. 7,071,336

Oxidation of the thebaine may alternatively be performed using potassiumdichromate in acetic acid⁹, performic acid¹⁰, hydrogen peroxide inacetic acid⁹ or peracetic acid¹¹. Improved yield, however, has beenreported to be obtained by oxidizing with m-chloroperbenzoic acid inacetic acid-trifluoroacetic acid mixture¹². ⁹ Freund et al, J. Prakt.Chem., 94, 135, (1916).¹⁰ Krassnig, Hederer, Schmidhammer, Arch. Pharm.Med. Chem., 1996, 325¹¹ Snuperak et al., WO 2006/019364 A1¹² Hauser etal., J. Med. Chem., 17, 1117 (1974) and Schwartz, U.S. Pat. No.4,795,813

14-Hydroxymorphinans have also been prepared from thebaine analoguesderived from codeine without a thebaine intermediate¹³.14-Hydroxycodeinone, the precursor to oxycodone, has been prepared fromcodeinone dienol acetate¹⁴ the ethyl dienol ether and the tert-butyldimethylsilyl dienol ether of codeinone⁵. ¹³ Schwarz & Schwartz, U.S.Pat. No. 4,472,253 and N D Wallace, J. Med. Chem., 24, 1525-1528,1981.¹⁴ B-S. Huang, Y. Lu, B-Y. Ji, A. S. Christodoulou U.S. Pat. No.6,008,355⁵ B. Mudryk, C. Sapino, A. Sebastian, EP 0889045 A1, U.S. Pat.No. 6,365,742 B1

The most common method for the conversion of 14-hydroxycodeinone tooxycodone is catalytic hydrogenation using a noble metal catalyst,preferably palladium, and hydrogen gas⁹. Reduction of14-hydroxycodeinone to oxycodone has also been performed usingdiphenylsilane and Pd(Ph₃P)/ZnCl₂ or with sodium hypophosphite inconjunction with a Pd/C catalyst in aqueous acetic acid.¹⁵ Oxycodone maybe prepared from thebaine by: dissolution of thebaine in aqueous formicacid, oxidation treatment with 30% hydrogen peroxide¹⁶, neutralizationwith aqueous ammonia to yield 14-hydroxycodeinone and hydrogenation ofthe 14-hydroxycodeinone in acetic acid with the aid of apalladium-charcoal catalyst.¹⁷ ⁹ Freund et al, J. Prakt. Chem., 94, 135,(1916).¹⁵ F-T Chiu, Y. S. Lo U.S. Pat. No. 6,177,567¹⁶ Seki, Chem.Pharm. Bull. 18, 671-676 (1970).¹⁷ Remington's Pharmaceutical Sciences,1041, (1975).

Oxycodone has also been prepared from thebaine bitartrate and codeinoneethyldienol ether by oxidation with hydrogen peroxide in formic acid andisopropanol, followed by catalytic hydrogenation⁵. Oxycodone has alsobeen prepared by the oxidation with peracetic acid of codeinone dienolsilylether in organic solvents to give 14-hydroxycodeinone, followed bycatalytic hydrogenation in acetic acid solution¹⁵. ⁵ B. Mudryk, C.Sapino, A. Sebastian, EP 0889045 A1, U.S. Pat. No. 6,365,742 B1¹⁵ F-TChiu, Y. S. Lo U.S. Pat. No. 6,177,567

During the oxidation of thebaine to give 14-hydroxycodeinone, severalby-products are formed. In particular,7,8-dihydro-8,14-dihydroxycodeinone (DHDHC) is formed by acid catalyzedaqueous hydrolysis of 14-hydroxycodeinone as shown in Scheme 1.

-   -   Reaction scheme of the process used to produce oxycodone from        thebaine

It was previously noted that DHDHC is easily converted to14-hydroxycodeinone¹⁸. This conversion occurs during the conversion ofoxycodone base to oxycodone hydrochloride, thus 14-hydroxycodeinone ispresent in the final oxycodone hydrochloride. Oxycodone hydrochloride isavailable from a number of suppliers including Noramco Inc., andMallinckrodt. Current commercially available oxycodone hydrochloride APIand oxycodone hydrochloride prepared by known procedures have levels of14-hydroxycodeinone of greater than 100 ppm. ¹⁸ Weiss. J. Org. Chem.,22, 1505, (1957)

Recent ICH guidelines suggest that there is a requirement for anoxycodone hydrochloride composition containing reduced amounts of14-hydroxycodeinone relative to current commercially available oxycodonehydrochloride.

14-Hydroxycodeinone belongs to a class of compounds known asα,β-unsaturated ketones. The class of compounds known as α,β-unsaturatedketones have been designated as potential gene-toxins¹⁹ due to theirsusceptibility to the Michael addition reaction (addition ofnucleophiles to the 1(β) position of an α,β-unsaturated ketone)²⁰. ¹⁹“Genotoxic impurities in Pharmaceuticals”, accepted for publication inRegulatory Toxicology and Pharmacology, Dec. 5, 2005.²⁰ March's AdvancedOrganic Chemistry, Jerry March and Michael B Smith, John Wiley & Sons2001, pages 1022-1024

A recent patent application assigned to Euro-Celtique discloses reducingthe levels of 14-hydroxycodeinone in oxycodone hydrochloride byre-submitting the product to conditions similar to those of the originalhydrogenation²¹. In addition to reduction by hydrogenation, theα,β-double bond adjacent to the carbonyl function can be reduced byother means such as transfer hydrogenation (using formic acid, isopropylalcohol, cyclohexene, indoline, sodium borohydride, tetrahydroquinoline,2,5-dihydrofuran, phosphoric acid or combinations thereof) and reductionby sodium hydrosulphite²². Dissolving metal reductions (zinc ormagnesium[Clemmenson reduction]) convert 14-hydroxycodeinone to a numberof products including mainly dihydrohydroxythebainone²³. In addition,the potential gene-toxin activity of α,β-unsaturated ketones can bemitigated by subjecting them to the type of reaction (Michael addition)which makes them potential gene-toxins in the first place. One of themost potent nucleophiles in biological systems is the thiol group (—SH),which is present in the amino acid cysteine, which in turn is common inproteins and often critical to protein folding and therefore itsbiological activity. Cysteine has been shown to react withα,β-unsaturated ketones at the 1(β) position of the double bond, therebysaturating the double and rendering it incapable to accept furthernucleophiles at this position and therefore no longer gene-toxic²⁴ ²¹ R.Chapman, L. S. Rider, Q. Hong, D. Kyle & R. Kupper, US 2005/0222188A1.²² M. Freund, E. Speyer, U.S. Pat. No. 1,479,293.²³ R. E. Lutz, L.Small, J. Org. Chem. 4, 220 (1939). See also Banerjee, A. K.; Alvarez,J.; Santana, M.; Carrasco, M. C. Tetrahedron, 1986, 42, 6615.²⁴ SeeCysteine conjugate of morphinone: Nagamatsu, Kunisuke; Kido, Yasumasa;Terao, Tadao; Ishida, Takashi; Toki, Satoshi; Drug Metabolism andDisposition (1983), 11(3), 190-4

14-hydroxycodeinone may also be formed during the conversion ofoxycodone base to oxycodone hydrochloride due to the conversion of DHDHCto 14-hydroxycodeinone by dehydration (see Scheme 1). The Euro-Celtiquepatent teaches that this conversion is promoted by excess hydrochloricacid and the ²⁵ resulting 14-hydroxycodeinone is converted to oxycodonehydrochloride by catalytic hydrogenation²¹. ²¹ R. Chapman, L. S. Rider,Q. Hong, D. Kyle & R. Kupper, US 2005/0222188 A1.

OBJECTS AND SUMMARY OF THE INVENTION

It is an object of certain embodiments of the present invention toprovide processes for reducing the amount of 14-hydroxycodeinone in anoxycodone base or oxycodone hydrochloride composition to an amount lessthan 100 ppm, preferably, less than 50 ppm, more preferably, less than10 ppm, and most preferably, less than 5 ppm.

Oxycodone base may be generated from thebaine or thebaine CPS usingperacetic acid in aqueous acetic acid, followed by palladium catalyzedhydrogenation.

In one embodiment of the present invention, the oxycodone base thusproduced is converted to the hydrochloride salt in water and an alcohol(e.g., butanol, methanol, 2-propanol) as solvent and the residual14-hydroxycodeinone is reduced from 25 to 100 ppm to less than about 5ppm using zinc or magnesium metal as the reducing agents.

In another embodiment of the present invention, levels of residual14-hydroxycodeinone in oxycodone base are rendered non gene-toxic byconversion to a thiol compound by reaction with a compound containing an—SH functionality (e.g., cysteine, sodium hydrosulfite, sodiumbisulfite, sodium metabisulfite, polymer bound alkyl thiol).

DETAILED DESCRIPTION OF THE INVENTION AND PREFERRED EMBODIMENTS

After considerable experimentation with different routes to oxycodonehydrochloride from thebaine CPS, the present inventors have discoveredmethods for manufacturing oxycodone hydrochloride with low (NMT 100,preferably, NMT 10 ppm) levels of 14-hydroxycodeinone in industriallyacceptable yields. The present invention overcomes many of the prior artproblems associated with higher (1000 to 3000 ppm) levels of14-hydroxycodeinone.

The present inventors have identified two strategies for producingoxycodone base or oxycodone hydrochloride suitable for conversion tofinal product oxycodone hydrochloride containing low levels of14-hydroxycodeinone. Firstly, preparation of a crude oxycodone base mustbe done in such a way as to generate low (less than 500 ppm) levels ofboth DHDHC and 14-hydroxycodeinone. This is achieved by the addition ofn-butanol to the mixture after preparation of the oxycodone base fromthebaine (see Scheme 1) to selectively remove impurities during theisolation step.

Secondly, a purification step where levels of both 14-hydroxycodeinoneand DHDHC are reduced by one or a combination of the following methods:

-   -   Dissolution of the oxycodone base in water and alcohol (e.g.,        butanol, methanol, 2-propanol) with excess hydrochloric acid and        then further reducing the 14-hydroxycodeinone levels by zinc or        magnesium metal reduction.    -   Dissolution of oxycodone base in hot n-butanol as solvent and        further reducing 14-hydroxycodeinone levels by treatment with        sodium hydrosulfite, cysteine or polymer-bound alkyl thiols.

Abbreviations used throughout this application shall have the meaning asset forth below:

-   -   COB crude oxycodone base    -   DHDHC 7,8-dihydro-8,14-dihydroxycodeinone    -   HPLC high performance liquid chromatography    -   ICH International Conference on Harmonization of Technical        Requirements for Registration of Pharmaceutical for Human Use    -   NMT no more than    -   USP United States Pharmacopeia

To provide a more concise description, some of the quantitativeexpressions given herein are not qualified with the term “about”. It isunderstood that whether the term “about” is used explicitly or not,every quantity given herein is meant to refer to the actual given value,and it is also meant to refer to the approximation to such given valuethat would reasonably be inferred based on the ordinary skill in theart, including approximations due to the experimental and/or measurementconditions for such given value.

The present invention is directed to a process for the preparation ofoxycodone base and/or oxycodone hydrochloride having low levels (e.g.,less than 50, preferably, less than 10 ppm) of 14-hydroxycodeinonecomprising: (a) heating a mixture of oxycodone base starting materialhaving more than 100 ppm of 14-hydroxycodeinone and between about 0.005and about 0.05 by weight of a sulfite compound selected from the groupconsisting of sodium hydrosulfite, sodium bisulfite, and sodiummetabisulfite in an alcohol/water solvent under basic conditions to atemperature of at least about 85° C. for at least about 30 minutes; and(b) isolating oxycodone base having less than 50 ppm, preferably, lessthan 10 ppm, of 14-hydroxycodeinone, provided that when the startingmaterial is oxycodone base, then step (a) is run under basic conditions(e.g., by adding sodium bicarbonate).

Preferably, the sulfite compound is sodium hydrosulfite, thealcohol/water solvent is n-butanol/water or isopropanol/water, and themixture of step (a) is heated for at least about 1 hour. Alternatively,the mixture of step (a) is heated to about 90° C. for about 2 hours. Theoxycodone base of step (b) may be isolated by cooling the mixture ofstep (a) to precipitate the oxycodone base having less than 10 ppm of14-hydroxycodeinone. The amount of the sulfite compound is preferablybetween about 0.03 and about 0.05 by weight as compared to the oxycodonebase or oxycodone hydrochloride starting material. In one embodiment,the oxycodone base starting material of step (a) has up to 2400 ppm of14-hydroxycodeinone.

In an embodiment, the present invention is directed to a process forpreparing oxycodone hydrochloride having less than 75 ppm, preferablyless than 10 ppm, of 14-hydroxycodeinone comprising: (a) stirring amixture of oxycodone base starting material having more than 100 ppm of14-hydroxycodeinone, with hydrochloric acid, and between about 0.005 andabout 0.05 by weight, preferably, between about 0.03 and about 0.05 byweight, of a metal powder selected from the group consisting of zincpowder and magnesium powder in an alcohol/water solvent for betweenabout 1 and about 5 hours; and (b) isolating oxycodone hydrochloridehaving less than 75 ppm, preferably less than 10 ppm, of14-hydroxycodeinone. Preferably, the metal powder is zinc powder, andthe mixture of step (a) is stirred for between about 3 and about 4hours. The oxycodone base starting material of step (a) may contain asmuch as 4900 ppm of 14-hydroxycodeinone.

In still another embodiment, the present invention is directed to aprocess for preparing oxycodone hydrochloride having less than 75 ppm,preferably less than 10 ppm, of 14-hydroxycodeinone comprising: (a)stirring a mixture of oxycodone hydrochloride starting material andbetween about 0.005 and about 0.05 by weight, preferably, between about0.03 and about 0.05 by weight, of a metal powder selected from the groupconsisting of zinc powder and magnesium powder in an alcohol/watersolvent for between about 1 and about 5 hours; and (b) isolatingoxycodone hydrochloride having less than 75 ppm, preferably less than 10ppm, of 14-hydroxycodeinone. Preferably, the metal powder is zincpowder, and the mixture of step (a) is stirred for between about 3 andabout 4 hours. The oxycodone base starting material of step (a) maycontain as much as 5000 ppm of 14-hydroxycodeinone.

A further embodiment of the present invention comprises a process forpreparing oxycodone hydrochloride having less than 70 ppm, preferablyless than 10 ppm, of 14-hydroxycodeinone comprising:

-   -   (a) heating a mixture of oxycodone hydrochloride starting        material having more than 100 ppm of 14-hydroxycodeinone, and        between about 0.005 and about 0.05 by weight of cysteine in an        alcohol/water solvent at a temperature between about 70 and        about 90° C. for between about 3 and about 6 hours; and    -   (b) isolating oxycodone hydrochloride having less than 70 ppm,        preferably less than 10 ppm, of 14-hydroxycodeinone. Preferably,        the cysteine is L-cysteine and the amount of the L-cysteine is        between about 0.03 and about 0.05 by weight. In another        embodiment, the alcohol is n-butanol and the oxycodone        hydrochloride isolated in step (b) has less than 10 ppm of        14-hydroxycodeinone.

Another embodiment of the present invention is directed to a process forpreparing oxycodone base having less than 50 ppm, preferably less than10 ppm, of 14-hydroxycodeinone comprising:

-   -   (a) heating a mixture of oxycodone base starting material having        more than 100 ppm of 14-hydroxycodeinone and between about 0.1        and about 0.5 by weight of a polymer bound alkyl thiol,        preferably, SiCH₂CH₂CH₂SH, in water at a temperature of from        about 20 to about 100° C. (preferably, about 70° C.) and at a pH        of from about 1 to about 7 (preferably, between about 5 and        about 6) for at least about 1 hour; and    -   (b) isolating oxycodone base having less than 50 ppm, preferably        less than 10 ppm, of 14-hydroxycodeinone. In a preferred        embodiment, the mixture of step (a) is heated from between about        1 and about 5 hours, preferably, for about 3 hours. The        oxycodone base of step (b) is preferably isolated by adjusting        the pH of the mixture of step (a) to between about 9 and about        10 and cooling to precipitate the oxycodone base having less        than 50 ppm, preferably less than 10 ppm, of        14-hydroxycodeinone.

In the processes of the present invention described above, the oxycodonebase or oxycodone hydrochloride starting material contains14-hydroxycodeinone as an impurity. The amount of 14-hydroxycodeinone inthe oxycodone base or oxycodone hydrochloride starting material is morethan 100 ppm and as much as 2500 ppm, 5000 ppm or even up to 10,000 ppm.

In the processes of the present invention, the amount of reactantspecified (e.g., sodium hydrosulfite, sodium bisulfite, sodiummetabisulfite, cysteine, zinc powder, magnesium powder, polymer boundalkyl thiol) is relative to the weight of oxycodone base or oxycodonehydrochloride starting material with impurities (14-hydroxycodeinone,DHDHC).

The processes described herein for reducing the amount of14-hydroxycodeinone in oxycodone base or oxycodone hydrochloridecompositions provide oxycodone base or oxycodone hydrochloride productwith less than 100 ppm, preferably, less than 50 ppm, more preferably,less than 10 ppm, and most preferably, less than 5 ppm of14-hydroxycodeinone.

In the processes of the present invention when an alcohol/water solventis used, any alcohol can be used. Examples of suitable alcohols includebutanol (n-butanol, t-butanol), propanol (isopropanol, n-propanol),ethanol, methanol and the like. Preferably, n-butanol is used. In theprocesses of the present invention (wherein a sulfite compound, zinc ormagnesium metal, cysteine or polymer bound alkyl thiol is used to obtainthe oxycodone base or oxycodone hydrochloride with reduced levels of14-hydroxycodeinone), the oxycodone base or oxycodone hydrochloridestarting material should be dissolved in the alcohol/water solvent (instep (a)). The selection of the alcohol, and the amounts of alcohol andwater to be used in the processes of the present invention may bereadily determined by one of ordinary skill in the art.

The present invention is also directed to a process for reducingimpurities in an oxycodone base composition comprising mixing oxycodonebase and n-butanol, adjusting the pH to between about 8.5 and about 12.0while maintaining the temperature at less than about 25° C., andisolating oxycodone base composition. The amount of n-butanol relativeto the oxycodone base starting material is between about 0.5 and about 5equivalents, preferably between greater than about 1 and about 5equivalents, most preferably, between about 2 and about 3 equivalents.The addition of n-butanol results in a two phase mixture and theoxycodone base precipitates when the reaction mixture is adjusted toalkaline pH. As a result, the oxycodone base gets washed by both theaqueous and organic phases of the mixture removing both aqueous- andbutanol-soluble impurities. The n-butanol is added after all of thechemistry (oxidation of thebaine or thebaine CPS to 14-hydroxycodeinoneand hydrogenation to oxycodone base) has been completed. It is addedbefore the isolation of the oxycodone base to improve the removal ofimpurities and color bodies from the thebaine or thebaine CPS, as wellas to reduce the level of process-generated impurities (e.g.,14-hydroxycodeinone, DHDHC). This process is particularly useful forremoving impurities when the starting material used to make oxycodonebase is thebaine CPS as compared to purified thebaine. In oneembodiment, the thebaine CPS may comprise a concentrate of poppy strawhaving a thebaine content of about 30 to about 85 weight % on a wet ordry weight basis, preferably, about 50 to about 83 weight % on a dryweight basis.

Example 1, which follows, describes a typical process for makingoxycodone base starting with purified thebaine without the addition ofn-butanol. As can be seen, the oxycodone base product isolated followingthe process of Example 1 contained at least 5.0% total impurities.Example 2, describes the process of the present invention for makingoxycodone base using n-butanol and starting with thebaine CPS whichcontains more impurities than the purified thebaine starting material ofExample 1. Surprisingly, the process of the present invention of Example2 provided oxycodone base containing a significantly reduced amount oftotal impurities, i.e., less than 3.5%, even though the thebaine CPSstarting material was used rather than purified thebaine.

In the processes of the present invention, the oxycodone base oroxycodone hydrochloride product is isolated according to known methods.For example, it may be isolated by evaporation of the solvent,precipitation (e.g., by cooling the reaction mixture to precipitate theproduct), filtration, by addition of an anti-solvent (i.e. a solventwhich affects precipitation of the product) to the reaction mixture orother suitable method. After isolation, the product may be dried usingconventional methods, for example, by heating in a vacuum oven.

The following Examples are set forth to aid in the understanding of theinvention, and are not intended and should not be construed to limit inany way the invention set forth in the claims which follow thereafter.

EXAMPLE 1 Production Scale Batch of Crude Oxycodone Base Manufacturedfrom Purified Thebaine

Water (421 kg), 90% formic acid (256 kg), and thebaine (300 kgs;Assay >98%) were added to a reactor. The temperature of the mixture wasadjusted to ≦25° C. 30% Hydrogen peroxide (123 kgs) was added to thereactor at 4-6 kg/min. The batch was heated to 50° C. and held at 48-60°C. for 4 hours±15 minutes. The batch was then sampled to test forcompletion of the reaction by HPLC and cooled to a temperature ≦15° C.

Catalyst (6.75 kgs of 5% Pd/C and moistened with 50% water; supplied byJohnson Matthey) was added to the mixture and the batch was hydrogenatedwith a pressure setpoint of 25 psig at a temperature ≦25° C. for 60±5minutes. The temperature of the batch was raised to 23±2° C. and thehydrogenation was continued for an additional 60±5 minutes. Additionalcatalyst (1.875 kgs) was added and hydrogenation was continued untilhydrogen uptake stops or for a maximum of 8 hours±15 minutes. The batchwas sampled for completion by HPLC and hydrogenation resumed for amaximum of 4 hours±15 minutes while waiting for laboratory results.

Upon completion of the hydrogenation, the batch was filtered through asparkler filter to portable intermediate bulk containers (IBC) to removethe spent catalyst. The batch was transferred to a crystallizer vessel.Half the batch (Part B) was transferred to a second crystallizer vessel.The temperature of the remaining batch (Part A) was adjusted to ≦30° C.The pH of Part A was adjusted to a 10.0-11.0 with 18% sodium hydroxide.Part A was cooled to ≦15° C. over 60±15 minutes and held at ≦15° C. fora minimum of 60 minutes. The precipitated product (COB Part A) wasisolated by centrifugation and each load was washed with water.

The temperature of Part B was adjusted to ≦30° C. The pH of the Part Bwas adjusted to a 10.0-11.0 with 18% sodium hydroxide. Part B was cooledto ≦15° C. over 60±15 minutes and held at ≦15° C. for a minimum of 60minutes. The precipitated product (COB Part B) was isolated bycentrifugation and each load was washed with water.

The yield of the crude oxycodone base was 84%. The total impurity levelsmeasured on a dry basis for Parts A and B were 5.0 and 5.3%respectively.

EXAMPLE 2 Laboratory Scale Batch of Crude Oxycodone Base Manufacturedfrom Thebaine CPS

Water (176 ml), 90% formic acid (88 ml), and thebaine CPS (155.2 g;124.5 g net weight of thebaine) were added to a reactor. The reactionmixture was filtered to remove insoluble material. The temperature ofthe mixture was adjusted to ≦25° C. 30% Hydrogen peroxide (50 ml) wasadded to the reactor over 10 to 15 minutes. The batch was heated to 50°C. and held at 50° C. for 4 hours. The batch was then sampled to testfor completion of the reaction by HPLC and cooled to ≦15° C. Activatedcarbon (12 g) was added to the mixture and stirred for 30 minutes at 30°C. At the end of this period, the activated carbon was removed byfiltration.

Catalyst (2.8 g of 5% Pd/C and moistened with 50% water; supplied byJohnson Matthey) was added to the mixture and the batch was hydrogenatedwith a pressure setpoint of 25 psig at 15° C. for 60±5 minutes. Thetemperature of the batch was raised to 23±2° C. and the hydrogenationwas continued for an additional 60±5 minutes. Additional catalyst (0.5g) was added and hydrogenation was continued until hydrogen uptake stopsor for a maximum of 8 hours±15 minutes. The batch was sampled forcompletion by HPLC and hydrogenation resumed for a maximum of 4 hours±15minutes while waiting for laboratory results.

Upon completion of the hydrogenation, the batch was filtered to removethe spent catalyst and the catalyst was washed with an additional 40 mlof water. The batch was transferred to a crystallizer vessel andn-butanol (135 ml) was added and the mixture was heated to 35° C. Sodiumhydroxide solution (50% w/w in water) was added slowly to a pH of 10 toprecipitate the product. The mixture was cooled to 15° C. over 2 hours,held at 15° C. for 30 minutes and the product was collected byfiltration. The product was washed with water (100 ml) to give 136 g wetoxycodone base (107.4 g dry basis; 85% yield). The product contained atotal impurity level of 3.41% (dry basis).

EXAMPLE 3

CPS Thebaine (170.57 g, Assay 88.8%, 151 g contained thebaine) wasdissolved in tap water (105 mL) and 56% acetic acid (103 mL). Thesolution was filtered to remove celite, which was rinsed with 60 mL oftap water. The filtrate was charged to a 1-L 4-neck jacketed reactorequipped with agitation, N₂ and thermocouple. Additional tap water (10mL) was used as a rinse while transferring the filtrate to the reactor.The solution was cooled to ˜−2 to −5° C. using a bath set at ˜−10° C.32% Peracetic acid (111 mL, 1.1 eqv. to thebaine) was then added to thereactor at a rate around 1 mL/min in a period of ˜1.5 to 2 hrs. (Theaddition rate can be adjusted, if needed, in order to maintain thereaction temperature below 2-5° C.). The reaction mixture was warmed upto 15-20° C. upon the completion of peracetic acid addition. Palladiumhydroxide (2.00 g) was added to the reaction mixture and it was stirredfor 2 hrs to decompose peroxides. The resulting mixture was transferredto a hydrogenator. n-Butanol (30 mL) was used to rinse the reactor andto avoid foaming. The hydrogenation was conducted at 50 Psi and 20-25°C. for 3 hrs. The spent catalyst was removed by filtration. The filtratewas charged to a 2-L 4-necked jacketed reactor. Activated carbon (15 g)and celite (4.5 g) were then added to the solution and stirred at 20-25°C. for 1 hr. The carbon and celite were filtered off and water (10-15mL) was used to wash the carbon and celite cake. The filtrate wascharged back to another 2-L 4-neck jacketed reactor. n-Butanol (200 mL)was added to the solution. The reaction mixture was cooled to 15° C. andthen the pH of the solution was adjusted from ˜4.0 to 11-11.5 using 50%NaOH solution (˜200 g). (The caustic addition rate was set at ˜15mL/min. However, the caustic addition was stopped when temperaturereached 25° C. and was resumed when temperature was back to ˜20° C.).The resulting mixture was stirred for an additional 15-30 min. Thesolids were then filtered off and washed with water (150 mL) followed byn-Butanol×2 (150 mL×2). The product was dried at ˜65° C. under vacuum toa constant weight (129.72 g). Yield: 86%.

The level of 14-hydroxycodeinone was 1414 ppm and the level of DHDHC was158 ppm.

EXAMPLE 4

Oxycodone base (36.2 g) prepared by the procedure outlined in Example 3containing 0.24% 14-hydroxycodeinone and 0.12% DHDHC by area, n-butanol(241 mL), and water (20.6 mL) were charged into a jacketed flask,equipped with condenser, mechanical stirrer additional funnel,thermocouple, and nitrogen-inlet adapter. The mixture was heated to atemperature of reflux (85° C.) to give a clear solution. Sodiumbicarbonate (1.0 g) and sodium hydrosulfite (1.5 g) in water (30 mL)were added into the butanol solution. The resulting mixture was stirredunder reflux for 1 hr. After the reaction was completed, the reactionmixture was cooled to 20-25° C. over 2 hr to allow product tocrystallize out. The product was filtered and washed with water (50 mL).The purified oxycodone base was dried under vacuum at a temperature of50-60° C. overnight to constant weight to give 22.7 g of oxycodone base.

The level of 14-hydroxycodeinone was 2 ppm and the level of DHDHC was 5ppm.

EXAMPLE 5

Oxycodone Hydrochloride (34.46 g) containing 0.16% 14-hydroxycodeinoneand 0.16% DHDHC by area, was dissolved in water (25 mL) and isopropylalcohol (138 mL) in a jacketed reactor. Sodium hydrosulfite (Na₂S₂O₄, 1g) was added to the solution and the mixture was heated to 90° C. andallowed to stir for 2 hr. The solution was then allowed to stir for 3days at 20-25° C. The solids were filtered and dried under vacuum in anoven to constant weight. Yield=70%.

The level of 14-hydroxycodeinone was 45 ppm and the level of DHDHC was 3ppm

EXAMPLE 6

Oxycodone base (40.07 g) containing 4869 ppm of 14-hydroxycodeinone and13.7 ppm DHDHC, was suspended in 1-butanol (250 mL) and water (180 mL)in a jacketed reactor. At 15° C. and with the reaction under nitrogen,aqueous hydrochloric acid (37%) was added to achieve a pH of 2.86. At25° C., zinc dust (1 g) was added and the resulting mixture was stirredfor 3 hr (Note: pH increased to ˜5.86 upon zinc powder addition).Activated carbon (Norit KB-G, 4 g) was added to the reactor and thesolution was allowed to stir for 40 min. The reaction mixture was thenfiltered to remove the zinc and carbon. The filtrate was charged to aclean reactor. The pH of the solution was adjusted to 6.17 usingpyridine (15 mL). Water was distilled off under vacuum at 60° C. Thesolution was then cooled to 20° C. and allowed to stir for 15 min. Thesolids were filtered and washed with 1-butanol (20 mL×2). The productwas dried to a constant weight at ˜65° C. under vacuum to yield 42.14 gof crude oxycodone hydrochloride.

The level of 14-hydroxycodeinone was 70.7 ppm and the level of DHDHC was52.9 ppm.

EXAMPLE 7

Oxycodone base (20.0 g) prepared by the procedure in Example 3 wassuspended in methanol (81 mL) and water (8 mL) in a 100 mL roundbottomed flask. At ambient temperature, 37% HCl (˜6.2 g) was added toachieve a pH of 2-3. Zinc dust (0.3 g) was then added and the resultingmixture was stirred for 3-4 hrs. (Note: pH increased to ˜6.5 upon Zincpowder addition). The reaction mixture was then filtered to remove theZinc dust and some significant solids that precipitated out during theZinc treatment. Active carbon (2.00 g) was added to the filtrate andstirred for 1 hr at ambient temperature. The carbon was removed byfiltration and methanol was removed by distillation under vacuum at20-25° C. 2-propanol (150 mL) was added to precipitate the oxycodonehydrochloride solids. The solids were filtered and dried to a constantweight at ˜65° C. under vacuum.

Yield: 83-85%.

The level of 14-hydroxycodeinone was 1.5 ppm and the level of DHDHC was50.7 ppm.

EXAMPLE 8

Oxycodone base (30.0 grams) prepared by the method in Example 3 andcontaining 2,500 ppm of 14-hydroxycodeinone, water (19.5 mL), and1-butanol (150 mL) were charged into a jacketed reactor under nitrogen,equipped with mechanical stirrer and thermocouple. The mixture washeated to a temperature of 72° C. with stirring. The pH of the solutionwas adjusted to 3.71 with Hydrochloric acid (37%). L-Cysteine (1.5 g,(R)-(+)-Cysteine or L-Cysteine, C₃H₇NO₂S, 97%) was added to the reactorand the pH dropped to 3.01. The solution was stirred at this temperaturefor 5.75 hr, and more L-Cysteine (0.5 g) was added. The solution wascooled to 50° C. and held overnight at 50° C. In the morning, thesolution was heated to 75° C. Water (11 mL) was removed by azeotropicdistillation under vacuum, and the solution was cooled to 20° C. Thesolids were filtered and dried in an oven under vacuum at 60° C. toconstant weight (29.97 g of dried Oxycodone Hydrochloride).

The level of 14-hydroxycodeinone was 2.5 ppm and the level of DHDHC was33 ppm.

EXAMPLE 9

Oxycodone hydrochloride (30.9 g), containing 0.16% 14-hydroxycodeinoneand 0.16% DHDHC by area, water (25 mL), and 2-propanol (138 mL) werecharged into a jacketed reactor, equipped with mechanical stirrer andthermocouple. L-Cysteine (1 g, (R)-(+)-Cysteine or L-Cysteine, C₃H₇NO₂S,97%)) was added to the reactor, and the mixture was heated to atemperature of 90° C. with stirring. The solution was stirred at thistemperature for 3 hr, and then cooled to 20° C. The solids were filteredand dried in an oven under vacuum at 60° C. to constant weight (25.79 g)to provide dried Oxycodone Hydrochloride.

The level of 14-hydroxycodeinone was 60 ppm and the level of DHDHC was 5ppm.

EXAMPLE 10

Oxycodone base containing 0.6 area % 14-hydroxycodeinone, (15.03 g),water (27 mL), and acetic acid (3.7 mL) were charged into a jacketedreactor, equipped with a magnetic stir bar and thermocouple. The mixturewas heated to a temperature of 70° C. with stirring. Concentrated H₂SO₄(1 drop) was added to the mixture to adjust pH to ˜5-6. Si-Thiol™ (4.84g, SiliCycle Company's SiliaBond Thiol™, R51030B, SiCH₂CH₂CH₂SH, 1.2mmol/g) was added to the mixture. Si-Thiol™ has a reactive thiol groupfunctionalized onto standard flash silica gel. The solution was stirredat this temperature for 3 hr, and then the Si-Thiol was removed byfiltration. The solids were rinsed with water. The filtrate was chargedto a clean reactor and 1-butanol (20 mL) was added to the solution. At50° C., sodium hydroxide (50%) was added to the mixture to adjust the pHto 9.0. The product was filtered, washed with water (10 mL) and dried inan oven under vacuum at 60° C. to constant weight (14.21 g) to provideoxycodone base.

The level of 14-hydroxycodeinone was 46 ppm.

EXAMPLE 11

Oxycodone base (14.69 g), containing 37 ppm 14-hydroxycodeinone, water(15 mL), and acetic acid (3.7 mL) were charged into a glass vial andallowed to stir until all dissolved. A Si-Thiol™ column was prepared(Silicycle Si-Thiol™ (7 g) and water slurry) and was heated to atemperature of 70° C. SiliCycle Company's SiliaBond Thiol™ (orSi-Thiol™, R51030B, SiCH₂CH₂CH₂SH) has a reactive thiol groupfunctionalized onto standard flash silica gel. Concentrated H₂SO₄ (2drops) was added to the solution in the glass vial. The solution wascharged to the Si-Thiol column and allowed to pass through the columnusing gravity (2 hr). Concentrated H₂SO₄ (2 drops) and water (6 mL) wasused to rinse the glass vial and this solution charged to the Si-Thiol™column. The solution collected from the column was charged to a cleanreactor and 1-butanol (20 mL) was added to the solution. The solutionwas heated to 50° C. and NaOH (50%) was added to the mixture to adjustthe pH to 9.5. After cooling to 15° C., the product was filtered, washedwith water (10 mL) and dried in an oven under vacuum at 60° C. toconstant weight (14.17 g) to provide oxycodone base.

The level of 14-hydroxycodeinone was 3 ppm.

EXAMPLE 12 Analytical Method

The analytical method described below was used to determine the amountof 14-hydroxycodeinone in each of the oxycodone base and oxycodonehydrochloride compositions prepared in Examples 3-11. This method wasalso utilized to determine the level of DHDHC in the oxycodone base andoxycodone hydrochloride compositions whenever the impurity level forDHDHC is provided (Examples 3-9).

Materials and Equipment

-   -   HPLC Grade Acetonitrile    -   HPLC Grade Water    -   Ammonium Hydroxide (28%)    -   Acetic Acid    -   Column: Varian, Polaris C18, 3 micron, 2.0 mm×150 mm, 3 micron,        Part #A2001-150X020 (www.varianinc.com)    -   Agilent 1100 Series HPLC, or equivalent. Equipped with a mass        spectrometric detector (Agilent Ion Trap XCT, or equivalent)    -   Analytical Balance    -   Reference Standard solids-

7,8 dihydro 14-hydroxycodeine 7,8 dihydro 8, 14-dihydroxycodeinoneOxycodone N-Oxide Oxycodone ethyl enolate 14-hydroxycodeinone

-   -   Test samples of oxycodone hydrochloride and oxycodone base        6.0 Procedure

6.1 Operating Parameters

-   -   Mass spectrometer, API Electrospray source settings:        Capillary—3000V, End Plate Offset—500V, nebulizer 40 psi, dry        gas 9 l/min, dry temp. 350 C    -   Mass spectrometer, lens and related voltages initially set by        SPS (Smart Parameter Setting) settings for m/z 314, then may be        optimized by direct infusion or observing oxycodone background        signals    -   For best results, the main oxycodone peak should be diverted        away from the electrospray source for the time window from        approximately 3 to 5 minutes. This window will need to be        adjusted depending upon the retention time for the        14-hydroxycodeinone peak, and will be set so that there is at        least 0.5 minutes between end of diversion and the        14-hydroxycodeinone peak.    -   Mass spectrometer, signal detection: ion trap set to scan m/z        290-500 with fragmentation turned off. For DHDHC, the extracted        ion chromatograms for m/z 332 (MH+) are normally used; in cases        where other adducts are visible, additional m/z values 354        (MNa+) and 370 (MK+) are added to the signal from m/z 332. For        14-hydroxycodeinone, the extracted ion chromatograms for m/z 314        (MH+) are normally used; in cases where other adducts are        visible, additional m/z values 336 (MNa+) and 352 (MK+) are        added to m/z 314.    -   Injection Volume: 2 μL    -   Column Temperature: 80 degrees Celsius    -   Elution mode: Isocratic    -   Flow Rate: 0.6 mL/minute    -   Run Time: 10 minutes    -   Flush column with 100% acetonitrile for 10 minutes once each day        during use.

6.2 Mobile Phase Preparation (5/95 acetonitrile water with 0.05% addedacetic acid/ammonium hydroxide)

-   -   Prepare 4 liters of the mobile phase by combining 200 mL of HPLC        grade acetonitrile with 2 mL ammonium hydroxide (28%), 2 mL        acetic acid, and 3800 mL of HPLC grade water.

6.3 Sample Diluent (20/80 acetonitrile/0.1N acetic acid in water)

-   -   The diluent will be prepared by adding approximately 6.0 grams        of acetic acid to a 1000 mL volumetric flask, followed by 200 mL        of HPLC grade acetonitrile, and bringing the volume to the 1000        mL mark by adding HPLC grade water.

6.4 Oxycodone Sample solutions

-   -   Accurately weigh 1.00±10% of Oxycodone base or HCl salt, and        transfer into a 100-mL volumetric flask. Dilute to volume with        diluent and mix well, assure full dissolution of sample. Sample        weights and solution volumes may be varied provided at least 100        mg of sample is used and the ratio of weight to volume is        maintained (i.e. 2 g/200 ml, or 0.5 g/50 ml).

Stock Impurity Standard Preparation (SIS; 0.5 mg/mL)

Accurately weigh 25 mg (±2 mg) of each standard, transfer to a common50-mL volumetric flask and dilute to volume with sample diluent. Mixwell and ensure full dissolution.

7,8 dihydro 14-hydroxycodeine 7,8 dihydro 8, 14-dihydroxycodeinone(DHDHC) Oxycodone N-Oxide Oxycodone ethyl enolate 14-hydroxycodeinone(14-HC)

Working Impurity Standard Preparation (WIS; 0.005 mg/mL)

Pipette 1-mL of the Stock Impurity standard into a 1000 mL flask anddilute to volume with sample diluent. Mix well to assure fulldissolution. The working impurity standard contains approximately 0.0005mg/mL of each specified impurity, corresponding to an impurityconcentration of 50 ppm in prepared samples.

6.5 Calculations

-   -   Peak identification is done by comparing the chromatogram of the        sample solution with that of the WIS solution, verifying the        observed MW's match that of the reference standard.    -   Eliminate blank peaks.    -   Measure the peak area of the DHDHC and 14-hydroxycodeinone        analytes in the chromatogram of the working impurity standard        (WIS).    -   Measure the peak area of analyte in the chromatogram of the        sample solution.    -   For oxycodone base samples calculate the concentration (in %,        w/w) of the analyte in the sample by the formula:

$c_{c,a} = {\frac{a_{c,s}}{a_{c,r}} \times \frac{c_{c,r}}{c_{a,s}} \times 100}$

-   -   -   where            -   a_(c,s)=peak area of analyte in the sample solution            -   a_(c,r)=peak area of analyte in the reference solution            -   c_(c,r)=concentration (in mg/mL) of analyte in the                reference solution            -   c_(a,s)=concentration (in mg/mL) of sample in the sample                solution

    -   For oxycodone HCl samples, calculate the concentration (in %,        w/w) of the analyte in the sample by the formula:

Weight Percent of Impurities

% I=(C _(std.) /C _(spl.))*(R _(i.) /R _(std.))*(MW-HCL Imp/MW-BaseImp)*100%

Where:

-   -   % SI=Percent Impurity    -   C_(std.)=Conc. of Imp. Std. Preparation calculated as Base, g/L    -   C_(spl.)=Conc. of Sample for Impurity Sample Preparation, g/L    -   R_(i)=Peak area response of individual impurity    -   R_(std.)=Peak area response of Imp. Standard Preparation    -   MW HCl Imp=Molecular weight of HCL form of impurity (see Table        below)    -   MW Base Imp=Molecular weight of Base form of impurity (see Table        below)

Impurity MW of HCl MW Base 7,8 dihydro 367.82 331.37 8,14-dihydroxycodeinone 14-hydroxycodeinone 349.80 313.35

6.6 System Suitability

-   -   6.6.1 System Precision: Acquire the chromatograms of six        consecutive injections of the Working Impurity Standard (WIS).        Calculate the relative standard deviation among the        14-hydroxycodeinone and DHDHC peak areas according to the        formula found in USP <621>.        -   The relative standard deviation among the peak areas must be            10%.    -   6.6.2 Tailing Factor: Calculate the tailing factor for the DHDHC        and 14-hydroxycodeinone peaks according to the equation found in        USP <621>.        -   The mean tailing factor for the peaks may not exceed 2.0.    -   6.6.3 Resolution: Calculate the resolution between the oxycodone        N-oxide and 14-hydroxycodeinone and 7,8 dihydro,        14-dihydroxycodeinone and 7,8 dihydro 8,14-dihydroxycodeinone        peaks using the equation found in USP <621>.        -   The USP resolution between the oxycodone N-oxide and            14-hydroxycodeinone and 7,8 dihydro, 14-dihydroxycodeinone            and 7,8 dihydro 8,14-dihydroxycodeinone peaks is ≧1.0.            Obtain resolution results from the Working Impurity Solution            (WIS).    -   6.6.4 S/N Ratio: Calculate the S/N ratio for the DHDHC and        14-hydroxycodeinone peaks. The mean S/N ratio for the peaks must        be equal to or greater than 10.

While the foregoing specification teaches the principles of the presentinvention, with examples provided for the purpose of illustration, itwill be understood that the practice of the invention encompasses all ofthe usual variations, adaptations and/or modifications as come withinthe scope of the following claims and their equivalents.

1. A process for preparing oxycodone hydrochloride having less than 70ppm of 14-hydroxycodeinone comprising: (a) heating a mixture ofoxycodone hydrochloride starting material having more than 100 ppm of14-hydroxycodeinone, and between about 0.005 and about 0.05 by weight ofcysteine in an alcohol/water solvent at a temperature between about 70and about 90 ° C. for between about 3 and about 6 hours; and (b)isolating oxycodone hydrochloride having less than 70 ppm of14-hydroxycodeinone.
 2. The process of claim 1, wherein the alcohol isn-butanol and the oxycodone hydrochloride isolated in step (b) has lessthan 10 ppm of 14-hydroxycodeinone.
 3. The process of claim 1, whereinthe cysteine is L-cysteine and the amount of the L-cysteine is betweenabout 0.03 and about 0.05 by weight.
 4. A process for preparingoxycodone base having less than 50 ppm of 14-hydroxycodeinonecomprising: (a) heating a mixture of oxycodone base starting materialhaving more than 100 ppm of 14-hydroxycodeinone and between about 0.1and about 0.5 by weight of SiCH₂CH₂CH₂SH in water at a temperature offrom about 20 to about 100 ° C. and at a pH of from about 1 to about 7for at least about 1 hour; and (b) isolating oxycodone base having lessthan 50 ppm of 14-hydroxycodeinone.
 5. The process of claim 4, whereinthe pH of step (a) is between about 5 and about
 6. 6. The process ofclaim 4, wherein the temperature of step (a) is about 70 ° C.
 7. Theprocess of claim 4, wherein the mixture of step (a) is heated frombetween about 1 and about 5 hours.
 8. The process of claim 7, whereinthe mixture of step (a) is heated for about 3 hours.
 9. The process ofclaim 4, wherein the oxycodone base of step (b) is isolated by adjustingthe pH of the mixture of step (a) to between about 9 and about 10 andcooling to precipitate the oxycodone base having less than 50 ppm of14-hydroxycodeinone.